Abstract

Tafamidis improves survival, reduces hospitalizations, and preserves quality of life and exercise tolerance for patients with cardiac amyloidosis.

Cardiac amyloidosis is a devastating diagnosis with a median survival of 2 to 4 years. Patients suffer from progressive heart failure due to deposition of proteinaceous material within the myocardial wall, leading to impaired ventricular relaxation and reduced contractility. Unfortunately, current therapies are restricted to symptomatic management. Aggregation of misfolded proteins into difficult-to-dissolve β-pleated sheets constitutes the underlying pathophysiology of cardiac amyloidosis, with aggregation of transthyretin (wild-type or mutant variants) and immunoglobulin light chains responsible for the vast majority of clinical cases. Transthyretin, which functions to transport thyroxine and vitamin A, is normally produced as a tetramer within the liver. Transthyretin amyloid protein is generated when transthyretin tetramers dissociate into monomers and misassemble into insoluble protein filaments and fibrils, a process that mechanistic studies have demonstrated can be suppressed by either mutations or small molecules that interfere with thyroxine binding sites within the native transthyretin protein. Based on these seminal findings, a small molecule therapeutic (tafamidis) was developed targeting the thyroxine biding sites of wild-type and mutant transthyretin variants.

The ATTR-ACT study investigators performed a multicenter, double-blind, placebo-controlled, randomized trial of 441 patients to test the hypothesis that inhibition of transthyretin disassembly is sufficient to improve outcomes for patients with transthyretin cardiac amyloidosis. This trial demonstrated that tafamidis improved survival, reduced cardiovascular hospitalizations, and preserved quality of life and exercise tolerance for enrolled patients with transthyretin cardiac amyloidosis. The study also provided important insights into how tafamidis might be best deployed in clinical practice. Reductions in cardiovascular hospitalizations and mortality were only observed 9 and 18 months following treatment, respectively. Additionally, patients with less severe disease displayed the greatest benefits. These findings are consistent with diminished amyloid deposition and delayed disease progression as the proposed mechanism of action and suggest that early diagnosis and intervention are paramount to successful disease management. Indeed, cardiac amyloidosis is underdiagnosed and may be responsible for a significant number of cases of presumed heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, and aortic stenosis.

Collectively, these findings provide hope for patients with cardiac amyloidosis. This study also opens the door to determining if other approaches to limit transthyretin amyloid production are effective, including small interfering RNAs, such as patisiran, and antisense oligonucleotides, such as inotersen.